Fanconi anemia is an autosomal recessive disease manifesting bone marrow failure with anemia, developmental abnormalities, chromosome instability and leukemia and other tumors. Cells from FA patients are hyper-sensitive to agents which make interstrand crosstinks (ICLS) and demonstrate abnormal chromosome forms, after ICL formation, including quadriradials and breaks. FA appears to be a defect in DNA repair or processing reflecting a failure to respond normally to intermediates of DNA replication, recombination or repair. The disease represents loss of function of any of at least nine proteins acting in a single pathway. Project 1 will investigate the function of the FANC proteins in genome stability and tumor suppression by analyzing chromatin remodeling as an explanation for the association of findings in FA. Chromatin remodeling is an essential function serving to make DNA accessible for gene regulation and repair The first aim of Project 1 is to test the hypothesis that the FA pathway interacts with chromatin remodeling to maintain genome stability and achieve tumor suppression. A second aim is to investigate the functional association of the FA pathway and the Bloom syndrome (BS) path. The BS path represents a genome stability function, and depletion of the Bloom protein (BLM) causes chromosome instability. We will test the hypothesis that BLM and the FANC proteins operate in a common pathway. Finally, the hypothesis of formation of a FANCD2 protein complex as the ultimate effector for the FA path will be investigated. This is plausible, since FANCD2 is mono-ubiquitinated (FANCD2-Ub) by the core FANC complex, a required step for FA action, but does not remain part of the FANC core: Interacting proteins may assemble to form the active complex, completing the FA pathway. The outcomes of our trials will allow us to identify the genome surveillance mechanisms defective in FA.